One of the most familiar aspects of the adaptive immune system is the body's ability to enjoy lifelong protection against a pathogen previously encountered through illness or vaccination--a phenomenon technically referred to as immunological memory. Despite dramatic advances in the field of immunology, basic questions remain unanswered concerning the generation and maintenance of immunological memory and the nature of the mechanisms that distinguish the body's response to the newly encountered pathogens ("primary response") from its response to one is has encountered before ("memory response"). The overall goal of the proposed research is to elucidate the specific biochemical signaling mechanisms underlying the generation, function, and maintenance of immunological memory. The achieve this goal, it is proposed to characterize signal transduction events triggered in vitro and in vivo in the centrally important CD4 T cell which controls and mediates immune responses. The research proposed has three specific aims. First, biochemical differences between memory CD4 T cells previously activated via contact of their T cell receptor (TCR) with antigenic ligand on an antigen presenting cell (APC), and naive CD4 T cells that have never encountered their specific antigen will be examined. Second, intracellular signaling processes leading to T cell activation in the presence of APC will be biochemically characterized using naive and memory CD4 T cells isolated phenotypically from normal inbred mice and from mice genetically engineered to express CD4 T cells of uniform antigen specificity. Third, the role of specific signaling intermediates in the generation and maintenance of a memory T cell response will be investigated in vivo, in mice deficient for particular intracellular kinases. This research has the potential to reveal molecular mechanisms operative in the adaptive immune response, either to enhance the memory immune response in vaccine or disease therapy, or suppress a particular type of response in treatments for autoimmune diseases.